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Antisense inhibition of microRNA-21 and microRNA-221 in tumor-initiating stem-like cells modulates tumorigenesis, metastasis, and chemotherapy resistance in pancreatic cancer
- Source :
- Targeted Oncology. 10:535-548
- Publication Year :
- 2015
- Publisher :
- Springer Science and Business Media LLC, 2015.
-
Abstract
- Our preliminary studies identified a small population side population (SP) cells in pancreatic cancer cells with stem cell-like properties, which were able to induce fast and aggressive tumor formation in nude mice. Gene expression analysis showed a significant difference in the expression of more than 1,300 genes in SP cells, among which a highly significant difference in microRNA expression of miR-21 and miR-221 between SP and NSP cells was identified. SP cells were identified and characterized by flow cytometry using Hoechst 33342 dye staining from a highly metastatic human pancreatic cancer cell line (L3.6pl). Antagomir transfection was performed using miRNA-21 and miRNA-221 antisense oligonucleotides (ASOs) and followed by detection of cell apoptosis, cell cycle progression, chemosensitivity, and invasion. Sorted SP cells from gemcitabine-resistant L3.6pl cells (L3.6pl(Gres)-SP) cells were orthotopically implanted in nude mice with or without miRNA-21 and miRNA-221 ASOs mono- and combination therapy. The administration of antagomir-21 and antagomir-221 significantly reduced the SP cell fraction, decreased SP cell differentiation, and downstream gene regulation, and thereby induced reduction of L3.6pl cell proliferation, invasion, and chemoresistance against gemcitabine and 5-Fluorouracil. Combination of ASOs therapy against miRNA-21 and miRNA-221 significantly inhibited primary tumor growth and metastasis compared to single antagomir treatment, especially, in L3.6plGres-SP-induced pancreatic tumor growth in vivo. These findings further indicate that the inhibition of miR-21 and miR-221 appear particularly suitable to target stem-like subpopulations and address their specific biological function to promote tumor progression in pancreatic cancer.
- Subjects :
- Male
Cancer Research
Carcinogenesis
Cellular differentiation
Mice, Nude
Biology
Transfection
medicine.disease_cause
Mice
chemistry.chemical_compound
Side population
Cell Line, Tumor
Pancreatic cancer
medicine
Animals
Humans
Pharmacology (medical)
Antagomir
Neoplasm Metastasis
Cell Proliferation
Mice, Inbred BALB C
Cell growth
Cell Differentiation
Oligonucleotides, Antisense
medicine.disease
Xenograft Model Antitumor Assays
Molecular biology
Up-Regulation
Pancreatic Neoplasms
MicroRNAs
Oncology
chemistry
Drug Resistance, Neoplasm
Tumor progression
Neoplastic Stem Cells
Subjects
Details
- ISSN :
- 1776260X and 17762596
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- Targeted Oncology
- Accession number :
- edsair.doi.dedup.....f40286b03885c5635aa3ebebf052c1aa